This competing continuation application proposes a set of patient studies of the serotonergic system in major depression and the effects of somatic antidepressants on the serotonergic system that builds on recent findings from patient studies of the biology of depression and from animal studies of the action of antidepressants. Recently, PET and SPECT studies have begun to provide more direct evidence in both bipolar and unipolar disorders that major depressive episodes are associated with serotonergic system abnormalities. In the current two plus years of funding, we have developed a method for quantifying 5- HT1A binding in human subjects in vivo using positron emission tomography (PET) and the ligand [11C]WAY-100635. We have acquired pilot data indicating lower regional brain 5-HT1A binding in depressed patients. We now propose to systematically investigate the neurobiology of a major depressive episode in both unipolar and bipolar disorders. To determine whether the biological changes associated with depression are reversible, we propose to study the short-term effects of antidepressant treatment, and also to examine a cohort of long-term, remitted and medication-free unipolar patients. In studying the action of antidepressants, we will compare depressed, unipolar patients from the baseline study above, after a six week course of an SSRI, paroxetine. The study of long-term recovered, drug-free patients will help distinguish the effects of recovery from the effects of treatment. The delayed therapeutic benefit of antidepressant medications such as SSRIs has been linked to delayed enhancement of intra-synaptic serotonin levels resulting from 5-HT1A autoreceptor downregulation found in animal studies. SSRIs (or serotonin transporter gene knockout) do not change post-synaptic terminal field 5-HT1A receptors, but downregulate the raphe autoreceptor. These observations have not been adequately tested in man because antidepressant actions on the 5-HT1A receptors may, at least partly, involve the same receptor population that is implicated in the pathogenesis of major depression, such effects need to be evaluated in patients. We propose to test these hypotheses directly in vivo using PET and the ligand [11C]WAY-100635, and to quantify the 5- HT1A receptor in healthy volunteers and patients with a major depressive episode.